SPORE in Brain Cancer

脑癌中的孢子

• 批准号: 10005119
• 负责人: Juan Fueyo
• 金额: $ 209.48万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005119
• 关键词: Adult; Alleles; Animals; Antibodies; Area; Attention; Award; Back; Bioinformatics; Biological; Biological Markers; Biometry; Blood; Brain Neoplasms; Caring; Clinic; Clinical; Clinical Trials; Collaborations; Data; Data Set; Development; Disease; Environment; Epigenetic Process; European; Fostering; Funding; Genetic; Genomics; Glioblastoma; Glioma; Glycolysis; Goals; Grant; Hispanics; Home environment; Human; Hypoxia; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; Impairment; Incidence; Incubators; K-Series Research Career Programs; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Mentors; Metabolic; Minority; Minority Groups; Mission; Molecular; Molecular Abnormality; Molecular Profiling; Mutation; Oncolytic viruses; Operative Surgical Procedures; Outcome; Oxidative Phosphorylation; Pathogenesis; Pathology; Patient-Focused Outcomes; Patients; Pattern; Phase I/II Clinical Trial; Phase II Clinical Trials; Phosphorylation Inhibition; Population; Population Study; Positron-Emission Tomography; Prognostic Marker; Radiation; Radiation Tolerance; Records; Research; Research Personnel; Research Project Grants; Resources; Risk; Safety; Sampling; Science; Single Nucleotide Polymorphism; Source; Stress; TNFSF4 gene; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Translating; Translational Research; University of Texas M D Anderson Cancer Center; Virus; Work; base; bench to bedside; biobank; cancer diagnosis; career; chemotherapy; epidemiology study; first-in-human; flexibility; genome wide association study; improved; improved outcome; inhibitor/antagonist; innovation; meetings; multidisciplinary; next generation; novel; oncolysis; oncolytic adenovirus; outcome forecast; personalized approach; phase II trial; population based; predictive marker; programs; racial disparity; repository; research clinical testing; response; success; targeted agent; targeted treatment; translational research program; translational scientist; treatment strategy; tumor; underserved minority

SUMMARY: OVERALL The overarching goal of this Brain Cancer SPORE renewal application is to improve the notoriously poor outcome of patients with glioblastoma (GBM). This goal will be achieved through the development of a multidisciplinary and highly translational research program that seeks to discover and rapidly translate novel and mechanistically diverse treatment strategies, including biological, immunological and targeted strategies, and by developing prognostic and predictive biomarkers that inform individualized approaches to GBM treatment, while also exploring pathogenesis and risk through genetic-based epidemiological studies in minority populations. By pursuing the strategies of this research program, all projects in the current funding period (2013-18) have successfully transitioned from the bench to clinical trials, including testing of a novel oncolytic virus, Delta-24- RGD, in multiple clinical trials; completing a biological-endpoint Phase II clinical trial of a PI3K-targeted agent, BKM-120; meeting IND requirements for a first-in-human trial of a new immune-modulatory p-STAT-3 inhibitor, WP1066; and validating prognostic biomarkers in clinical trial datasets, while also testing a molecular predictor of radiation sensitivity. In this renewal application we propose three translational research projects that organically evolved from the successes of our current SPORE, and which are supported by four mission-critical Cores (Administrative, Pathology/Biorepository, Biostatistics/ Bioinformatics, Animal). Our Developmental Research Program (DRP) and Career Enhancement Program (CEP) continue as incubators of new projects and portals for new investigators. The aims of our projects are: Project 1: Exploit the capacity of Delta-24-RGD to activate anti-glioma immunity by completing a clinical trial combining Delta-24-RGD with Pembrolizumab, and by testing next-generation Delta-24-RGD viruses that are armed with immune stimulatory molecules: OX40L, GITRL, and 4-1BBL, while analyzing anti-Ad5 antibodies as a biomarker in response to therapy. Project 2: Attack metabolic vulnerabilities of GBMs through the development and clinical testing of a novel inhibitor of oxidative phosphorylation (OxPhos), IACS-010759, that efficiently kills GBMs harboring genetic or epigenetic mutations that impair glycolysis (e.g. ENO1 deletions), and by evaluating a new hypoxia-responsive PET probe, 18F-FAZA, as a readout of OxPhos inhibition and target engagement of IACS-010759. Project 3: Decipher germline and somatic genomic landscape of gliomas in Black and Hispanic minority populations, whose prognosis and survival differ than GBM patients of White European descent. Germline SNP data will be combined with extensive molecular profiling in case-matched tumors. A detailed analysis will be performed to determine ancestry composition and how it influences risk for gliomas and clinical outcome in minorities.

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